Hereditary pheochromocytoma-paraganglioma is a term encompassing several distinct genetic disorders in which the two respective tumors appear. Mutations in succinate dehydrogenase (SDH) genes seem to play a pivotal role in the pathogenesis. Typical manifestations arise from excessive catecholamine secretion - hypertension, headaches, diaphoresis, anxiety, and palpitations are some of the most common. The detailed patient history, physical examination, biochemical tests, and imaging and genetic studies should be used to make an early diagnosis as a significant risk exists toward a malignant transformation of tumors and their metastatic spread.
The clinical presentation of hereditary pheochromocytoma-paraganglioma mainly depends on the secretory properties of the two tumors. A pheochromocytoma, arising from the adrenal medulla, almost always secretes catecholamines, whereas paragangliomas (arising from paravertebral neuroendocrine tissues) can be either parasympathetic and nonsecretory, or sympathetic and produce catecholamines as well    . The main feature of catecholamine hypersecretion is paroxysmal hypertension, which is encountered in virtually all patients    . Palpitations, tachycardia, arrhythmia, headaches, bouts of diaphoresis, and anxiety attacks are other frequent manifestations of this disease   . These manifestations are often induced when the individual changes his/her body position (for example, from sitting to standing) but surgery, exercise, and drug-induced manipulations of blood pressure may also serve as promoting factors   . Painless hematuria could be observed if paragangliomas are located within the urinary bladder wall . On the other hand, the cranial or neck localization of paragangliomas can result in a unilateral hearing loss, tinnitus, dysphagia, localized pain, impaired tongue movement, or even cough or hoarseness due to the mass effect of the spreading tumor . Head and neck paragangliomas, however, are rarely secretory and are much less likely to produce catecholamine-related symptoms    .
Entire Body System
Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP. [ghr.nlm.nih.gov]
Eur J Nucl Med Mol Imaging. 2016; 43 :1784–91. [ PubMed : 26996779 ] Jasperson KW, Kohlmann W, Gammon A, Slack H, Buchmann L, Hunt J, Kirchhoff AC, Baskin H, Shaaban A, Schiffman JD. [ncbi.nlm.nih.gov]
Barnes L, Tse LLY, Hunt JL, Michaels L. In:BarnesL, EvesonJW, ReichartP,SidranskyD (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. IARC Press: Lyon 2005, pp. 362-3. [atlasgeneticsoncology.org]
On the other hand, the cranial or neck localization of paragangliomas can result in a unilateral hearing loss, tinnitus, dysphagia, localized pain, impaired tongue movement, or even cough or hoarseness due to the mass effect of the spreading tumor. [symptoma.com]
Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. [blueprintgenetics.com]
[…] phenotypes Inheritance ClinVar HGMD FH Hereditary leiomyomatosis and renal cell cancer AD/AR 178 207 MAX Pheochromocytoma AD 13 31 NF1 * Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome AD 1157 2901 RET Hirschsprung disease, Central hypoventilation [blueprintgenetics.com]
Palpitations, tachycardia, arrhythmia, headaches, bouts of diaphoresis, and anxiety attacks are other frequent manifestations of this disease. [symptoma.com]
We experienced an 18-year-old woman who complained of severe headaches in whom hypertension was revealed. She was suspected of having a malignant tumor based on her clinical characteristics, despite showing no evidence of metastatic lesions. [ncbi.nlm.nih.gov]
The doctor should pay special attention to symptoms such as high blood pressure, heart palpitations, anxiety, headache, coughing, hoarse voice, problems swallowing and hearing loss. [stjude.org]
Hypersecretion manifests as sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor and apprehension or anxiety. [orpha.net]
The medical history should include symptoms of catecholamine excess, such as elevation in blood pressure, headaches, diaphoresis, and palpitations, and also symptoms attributable to mass effect, such as dysphagia, hearing loss, and dysarthria. [clincancerres.aacrjournals.org]
Because of the potential for malignant transformation of both pheochromocytomas and paragangliomas in this hereditary syndrome, it is critical to establish an early diagnosis. With a properly obtained patient history and a detailed physical examination, the physician can obtain sufficient information to indicate further testing. In addition to the onset of symptoms, as well as their course and progression, the patient interview might reveal incompletely explained sudden death within the family, which may favor a hereditary component in the presumptive diagnosis . During the physical examination, tachyarrhythmia and blood pressure changes can be observed .
Imaging studies are the cornerstone in recognizing the etiology of the disease. Computed tomography (CT) and magnetic resonance imaging (MRI) are the two main imaging procedures that are able to visualize the tumor location  . MRI, but also 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT scanning and 123I-metaiodobenzylguanidine (MIBG) scintigraphy are used for the detection of metastatic disease  .
Biochemical studies should be carried out to determine the concentration of catecholamines in the circulation. Measurements of serum free or urinary fractioned metanephrines through liquid chromatography-mass spectrometry (LC-MS) is regarded as the optimal laboratory procedure .
Finally, a distinction between different disorders where these two tumors appear is achieved through genetic studies. Revealed mutations of specific succinate dehydrogenase (SDH) genes are main criteria used to confirm the diagnosis of hereditary pheochromocytoma-paraganglioma  .
- Kirmani S, Young WF. Hereditary Paraganglioma-Pheochromocytoma Syndromes. 2008 May 21 [Updated 2014 Nov 6]. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
- Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915–1942.
- Lefebvre M, Foulkes WD. Pheochromocytoma and paraganglioma syndromes: genetics and management update. Curr Oncol. 2014;21(1):e8-e17.P
- Pasini B, Stratakis CA. SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma–paraganglioma syndromes. J Intern Med. 2009;266:19–42.
- Fishbein L, Nathanson KL. Pheochromocytoma and Paraganglioma: Understanding the Complexities of the Genetic Background. Cancer Genet. 2012;205(1-2):1-11.
- Gill AJ, Pachter NS, Clarkson A, et al. Renal tumors and hereditary pheochromocytoma-paraganglioma syndrome type 4. N Engl J Med. 2011;364(9):885-886.